Document Type

Thesis - Open Access

Award Date

2023

Degree Name

Master of Science (MS)

Department / School

Pharmaceutical Sciences

First Advisor

Jayarama Gunaje

Abstract

Nature offers many sources such as fruits, beverage crops, vegetables, herbs, spices, tea, dark chocolate, and wine, that are rich in hydroxybenzoic acids (HBAs). They are a prominent phenolic acids with excellent biochemical and antioxidant properties. Due to the vast dietary health benefits of HBAs such as anti-inflammatory, anti-allergenic, immunoregulatory, antimicrobial, antithrombotic, antidiabetic, anticancer properties and cardioprotective capabilities, they are attracting the attention of physicians and researchers alike to understand their mechanisms of action. It is anticipated that the understanding of the role of HBAs for their greater use in diet/supplements is beneficial to reverse common illnesses such as inflammation, cardiovascular diseases, diabetes, and cancer. Hydroxybenzoic acids are compounds that contain a carboxylic group and one or more of OH groups, attached to the benzene ring. The most extensively studied HBA is salicylic acid (2-hydroxybenzoic acid; 2-HBA), which is abundantly present in plants such as the willow tree. The other plant derived HBAs studied include 2,3-dihydrobenzoic acid (2,3-DHBA, pyrocatechuic acid), 2,4-dihydroxybenzoic acid (2,4-DHBA, b-resorcyclic acid), 2,5-dihydroxybenzoic acid (2,5-DHBA, gentisic acid), 2,6- dihydroxybenzoic acid (2,6-DHBA, g-resorcyclic acid), 3,4- dihydroxybenzoic acid (3,4-DHBA, proto-catechuic acid), 3,5- dihydroxybenzoic acid (3,5-DHBA, a-resorcyclic acid), 3,4,5- Trihydroxybenzoic acid (3,4,5-THBA, gallic acid), and 2,4,6- trihydrobenzoic acid (2,4,6-THBA). All these are secondary metabolites present in plants in either free form or conjugated with other compounds. Hydroxybenzoic acids are also produced from parent compounds such as flavonoids, though an increase in temperature while heating/cooking, spontaneous degradation, or through microbial degradation in the gastrointestinal tract. It is believed that consumption of a diet rich in fruits and vegetables has immense health benefits including the prevention of colorectal cancer. Literature is enormous on the ability of flavonoids to decrease the occurrences of colorectal cancers; however, the mechanisms are not clearly established. Some researchers proposed that the parent flavonoid compounds directly act on specific proteins on target cells to inhibit cell growth; however, other researchers propose that the HBAs produced from the degradation of flavonoids are responsible for the observed growth inhibitory properties. Since flavonoids are relatively unstable compounds and can easily degrade to generate HBAs, it is likely that HBAs are major contributors to inhibition of cancer cell growth. Studies in our laboratory have demonstrated that several of the HBAs show growth inhibitory properties on colon cancer cell growth in vitro. Hydroxybenzoic acids also appear very selective in their action. For example, 2,4,6-THBA, 3,4,5- THBA, 3,4-THBA and 2,5-THBA showed the capacity to inhibit HCT-116 and HT-29 colon cancer cell growth; the inhibitory properties were not observed when 2,4-DHBA, 2,6-DHBA and 4-HBA were used in in vitro experiments. This suggested that the number and position of OH groups in the benzoic acid structure are important determinants in HBAs ability to inhibit cancer cell growth. Sensitivity of the cancer cells to HBAs were also different, for example, complete inhibition of the HCT-116 cells required 250 μM concentration of 3,4-DHBA; interestingly, with 3,4,5-THBA, only 30 μM concentration of the compound was sufficient to cause complete inhibition (32). 2,3,4-THBA is a plant metabolite present in several fruits and vegetables including Adzuki beans. This bean variety is a major cultivar in southeast Asia. Information on the ability of 2,3,4-THBA to inhibit cancer cell growth was not available in literature until we started this study. Based on the data available from our laboratory on other HBAs, we hypothesized that 2,3,4-THBA may have the ability to inhibit cancer cell growth. The present study was carried out as a part of a pilot study to determine the ability of 2,3,4-THBA to inhibit the growth in HCT 116 colon cancer cells and MDA-MB-231 breast cancer cells. We observed that 2,3,4-THBA is a potent inhibitor of cell growth in both HCT-116 and MDA-MB-231 cells, although a greater sensitivity of this compound was observed in MDA-MB-231 cells as compared to HCT-116 cells. Consistent with growth inhibition, in HCT- 116 cells, treatment with 2,3,4-THBA caused an increase in cyclindependent kinase inhibitors, p27 and p21. Although the observations require additional studies to confirm the findings, the data suggest that 2,3,4-THBA present in plants exhibits cancer cell growth inhibitory properties, and therefore has the potential for additional investigations as an anti-cancer agent.

Publisher

South Dakota State University

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Rights Statement

In Copyright